The objective of this project is to define novel molecular mechanisms by which nuclear receptors modulate lipid homeostasis. Given the central roles that metabolism plays in diseases such as atherosclerosis and diabetes, elucidating novel lipid signaling pathways may uncover new opportunities for therapeutic intervention, and will advance our understanding of fundamental physiological and pathophysiological processes. For the past 15 years, this grant has focused on understanding the mechanism of action of LXR nuclear receptors. Work from this project has identified LXRs and several of their downstream genes as potential targets for the modulation of human lipid metabolism. In the current grant cycle, we characterized the structure and physiology of IDOL, an E3 ubiquitin ligase who activity is controlled by LXRs. The current application is centered on novel RNA mediators of LXR and their roles in the control of gene expression and systemic lipid homeostasis. We have identified two novel long non-coding (lnc) RNAs that are regulated by LXRs in a tissue-selective manner, suggesting that they perform context-specific functions in metabolism. LeXis (Liver-expressed LXR-induced sequence) is highly responsive to LXR activation in liver, whereas MeXis (Macrophage- expressed LXR-induced sequence) is selectively expressed in macrophages. Preliminary data show that LeXis lowers plasma cholesterol levels by selectively targeting SREBP-2 pathway genes involved in sterol synthesis, and that MeXis functions in cis to modulate Abca1 expression in a cell type- selective manner. Aim 1 is to determine the function and mechanism of action of the lncRNA LeXis in hepatic lipid metabolism. Aim 2 is to determine the function and mechanism of action of the lncRNA MeXis in macrophage biology. Aim 3 is to test the impact of physiological and pharmacological lncRNA expression on atherosclerosis. We have developed knockout models for both LeXis and MeXis and have validated state-of-the art mechanistic approaches to deciphering their mechanisms of action. Understanding the mechanisms by which LXRs regulate lipid homeostasis through control of lncRNA expression will bring fundamental insights relevant for the treatment or prevention of metabolic disease.